Benign prostatic hypertrophy

ABSTRACT

The present invention provides novel uses of compounds of general formula I ##STR1## wherein R 1 , R 4  and R 5  are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R 2  and R 3  are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hypertrophy

Use of 3,4-diphenyl chromans for the manufacture of a pharmaceuticalcomposition for the treatment or prophylaxis of benign prostatichypertrophy

This application claims priority under 35 U.S. C. §119(e) of provisionalapplication 60/009,905, filed Jan. 11, 1996, the contents of which areincorporated herein by reference.

FIELD OF THIS INVENTION

The present invention relates to the use of compounds of the generalformula I for the treatment of patients suffering from benign prostatichypertrophy and prophylaxis hereof. The present invention also embracespharmaceutical compositions comprising these compounds and methods ofusing the compounds and their pharmaceutical compositions.

BACKGROUND OF THIS INVENTION

Benign prostatic hypertrophy is an almost universal phenomenon in agingmen. It refers to a nodular enlargement of the gland due to hyperplasiaof both glandular and stromal components. The incidence of this diseaseis only 8% during the fourth decade, but it reaches 50% in the fifthdecade and 75% in the eighth decade. The disorder is not a major causeof death, but it is a leading cause of morbidity in elderly men. Thepathogenesis is not well-understood, but dihydrotestosterone togetherwith increasing levels of estrogen which occur in men actsynergistically to induce prostatic growth. The treatment is surgical,which, however, can only be offered to a small selected number ofpatients with this disease because the majority of men above age 60 havesome degree of prostatic hyperplasia. No protecting factors other thancastraction have been identified and no effective pharmacologicaltreatment or profylaxis exists.

Centchroman is a non-steroidal compound known to have antiestrogenicactivity. It is in use in India as an oral contraceptive (see, forexample, Salman et al., U.S. Pat. No. 4,447,622; Singh et al., ActaEndocrinal (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289;Indian Patent Specification No. 129187). Centchroman has also beeninvestigated as an anti-cancer agent for treatment of advanced breastcancer (Misra et al., Int J Cancer 43 (1989), 781-783. Recently,centchroman as a racemate has been found as a potent cholesterollowering pharmaceutical expressed by a significant decrease of the serumconcentrations (S. D. Bain et al., J Min Bon Res 9 (1994), S 394).

U.S. Pat. No. 5,453,442 describes methods of lowering serum cholesteroland inhibiting smoother muscle cell proliferation in humans andinhibiting uterine fibroid disease and endometriosis in women byadministering compounds of formula I as shown therein. Furthermore, U.S.Pat. No. 5,280,040 describes methods and pharmaceutical compositions forreducing bone loss using 3,4-diaryl chromans and their pharmaceuticallyacceptable salts. There is no disclosure in the patents of using thecompounds to treat or prevent benign prostatic hypertrophy.

One object of the present invention is to provide compounds which caneffectively be used in the treatment or prophylaxis of benign prostatichypertrophy.

BRIEF DESCRIPTION OF THIS INVENTION

It has, surprisingly, been found that compounds of the general formula Ias stated in claim 1 can be used in the treatment or prophylaxis ofbenign prostatic hypertrophy.

DETAILED DESCRIPTION OF THIS INVENTION

The present invention is based in part on the discovery that arepresentative 3,4-diarylchroman, centchroman(3,4-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy)phenyl!-7-methoxychroman) is effective againstbenign prostatic hypertrophy, inter alia in rats. An increased prostateweight is the cardinal observation seen in patients with prostatichypertrophy, hence these data thus indicate that the 3,4-diarylchromansare useful as therapeutic agents against benign prostatic hypertrophy inmammals, including primates such as humans.

Within the present invention, compounds of formula I as stated in claim1 are used for benign prostatic hypertrophy in a patient. Within formulaI, R¹, R⁴ and R⁵ are individually hydrogen, hydroxy, halogen,trifiuoromethyl, lower alkyl, lower alkoxy or (tertiary amino)(loweralkoxy); and R² and R³ are individually hydrogen or a lower alkyl. Asused herein, the term "lower alkyl" includes straight and branched chainalkyl radicals containing from 1 to 6 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl,n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "loweralkoxy" includes straight and branched chain alkoxy radicals containingfrom 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy,2-ethylbutoxy, 2,3-dimethylbutoxy and the like. "Halogen" includeschloro, fluoro, bromo and iodo. Herein, the term "(tertiary amino)(loweralkoxy)" is a lower alkoxy group which is substituted by a tertiaryamino radical. The tertiary amino radical may be a N,N-dialkylamine suchas a N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino andN,N-dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine,N-methylpiperazine or morpholine. Preferred compounds include those inwhich R¹ is lower alkoxy; R² and R³ are lower alkyl, especially methyl;R⁴ is hydrogen; and R⁵ is (tertiary amino)(lower alkoxy) of thepolymethyleneimine type. Within particularly preferred embodiments, R¹is in the 7-position and is lower alkoxy, particularly methoxy; each ofR² and R³ is methyl, R⁴ is hydrogen, and R⁵ is in the 4-position and isa (tertiary amino)(lower alkoxy) radical such as2-(pyrrolidin-1-yl)ethoxy. To be included by this invention are allpharmaceutically acceptable salts of the mentioned compounds of formulaI.

It is preferred to use the compounds of formula I in thetransconfiguration. These compounds may be used as racemic mixtures, orthe isolated d- or l- enantiomers may be used. The trans-I-enantiomersare more preferred.

A particularly preferred compound for use within the present inventionis centchroman having the formula IV as stated in claim 11.

Although only one enantiomer is shown, it will be understood that theformula IV is used herein to designate the transconfiguration of the3-and 4-phenyl groups and that both the d- and I-enantiomers, as well asthe racemic mixture, are included.

3,4-diarylchromans are prepared according to known methods, such asthose disclosed in U.S. Pat. No. 3,340,276 to Carney et al., U.S. Pat.No. 3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276-279,the contents of which are incorporated herein by reference. Conversionof the cis isomer to the trans configuration by means of anorganometallic base-catalyzed rearrangement is disclosed in U.S. Pat.No. 3,822,287. The optically active d- and l-enantiomers may be preparedas disclosed by Salman et al. in U.S. Pat. No. 4,447,622 (incorporatedherein by reference) by forming an optically active acid salt which issubjected to alkaline hydrolysis to produce the desired enantiomer. IfR2 is different from R3 and R4 is different from R5, the general formulaI covers 8 optical isomers.

Within the present invention, 3,4-diarylchromans of formula I may beprepared in the form of pharmaceutically acceptable salts, especiallyacid-addition salts, including salts of organic acids and mineral acids.Examples of such salts include salts of organic acids such as formicacid, fumaric acid, acetic acid, propionic acid, glycolic acid, lacticacid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaricacid, citric acid, benzoic acid, salicylic acid and the like. Suitableinorganic acid-addition salts include salts of hydrochloric,hydrobromic, sulphuric and phosphoric acids and the like. The acidaddition salts may be obtained as the direct products of compoundsynthesis. In the alternative, the free base may be dissolved in asuitable solvent containing the appropriate acid, and the salt isolatedby evaporating the solvent or otherwise separating the salt and solvent.3,4-diarylchromans of formula I and their salts are useful within humanand veterinary medicine, for example, in the treatment of patientssuffering from benign prostatic hypertrophy. For use within the presentinvention, 3,4-diarylchromans of formula I and their pharmaceuticallyacceptable salts are formulated with a pharmaceutically acceptablecarrier to provide a medicament for parenteral, oral, nasal, rectal,subdermal or intradermal or transdermal administration according toconventional methods. Formulations may further include one or morediluents, fillers, emulsifiers, preservatives, buffers, excipients, etc,and may be provided in such forms as liquids, powders, emulsions,suppositories, liposomes, transdermal patches, controlled release,derreal implants, tablets, etc. One skilled in this art may formulatethe compounds of formula I in an appropriate manner, and in accordancewith accepted practices, such as those disclosed in Remington'sPharmaceutical Sciences, Gennaro, ed., Mack Publishing Co., Easton, Pa,1990.

Oral administration is preferred. Thus, the active compound of formula Iis prepared in a form suitable for oral administration, such as a tabletor capsule. Typically, a pharmaceutically acceptable salt of thecompound of formula I is combined with a carrier and moulded into atablet. Suitable carriers in this regard include starch, sugars,dicalcium phosphate, calcium stearate, magnesium stearate and the like.Such compositions may further include one or more auxiliary substances,such as wetting agents, emulsifiers, preservatives, stabilizers,colouring additives, etc.

Pharmaceutical compositions containing a compound of formula I may beadministered one or more times per day or week. An effective amount ofsuch a pharmaceutical composition is the amount that provides aclinically significant effect against benign prostatic hypertrophy. Suchamounts will depend, in part, on the particular condition to be treated,age, weight, and general health of the patient, and other factorsevident to those skilled in the art. A typical daily dose will contain anontoxic dosage range of from about 0.001 to about 75 mg/kg patient perday of a compound of the present invention, preferably in a range fromabout 0.01 to 75, more preferably in the range from about 0.01 to 50,and especially in the range from about 0. 1 to 25, mg/kg patient perday.

The pharmaceutical compositions containing a compound of formula I maybe administered in unit dosage form one or more times per day or week.In the alternative, they may be provided as controlled releaseformulations suitable for dermal implantation. Implants are formulatedto provide release of active compound over the desired period of time,which can be up to several years. Controlled-release formulations aredisclosed by, for example, Sanders et al., J Pharm Sci 73 (1964),1294-1297, 1984; U.S. Pat. No. 4,489,056; and U.S. Pat. No. 4,210,644,which are incorporated herein by reference.

The following examples are offered by way of illustration, notlimitation.

Examples of preferred compounds of formula I are centchroman as aracemic mixture and as isolated I-centchroman and d-centchromanenantiomers. Furthermore, 3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl-7-hydroxychroman is a preferredcompound. The more preferred compound is isolated I-centchroman(I-3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl!-7-methoxychroman).

Examples of pharmaceutically acceptable acid addition salts are saltswith non-toxic acids, either inorganic acids such as hydrochloric acid,sulphuric acid and phosphoric acid, or organic acids such as formicacid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconicacid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonicacid, methanesulphonic acid and malonic acid.

The present invention is further illustrated by the following exampleswhich, however, are not to be construed as limiting the scope ofprotection. The features disclosed in the foregoing description and inthe following examples may, both separately and in any combinationthereof, be material for realising the invention in diverse formsthereof.

EXAMPLE 1

Sixty sexually mature male Sprague-Dawley rats were assigned to one ofthe following five treatment groups (12 rats per group): 1)saline, 2)I-centchroman 0.025 mg/kg/day, 3) I-centchroman 0.125 mg/kg/day, 4)I-centchroman 0.625 mg/kg/day and 5)I-centchroman 3.125 mg/kg/day. Thedoses were administered three times per week for 13 weeks by oralgavage. At the conclusion of the experiment and autopsy was performed,the prostate gland and testes were isolated and weighed. L-centchromanhad no effect on the average testis weight between the groups. However,a marked and dose-dependent effect on the prostate gland was observed asillustrated in Table 1.

                  TABLE 1                                                         ______________________________________                                        Effect of I-centchroman on prostate gland weight in Sprague-                  Dawley rats                                                                   Treatment             Prostate gland (g)                                      ______________________________________                                        Saline                0.639 ± 0.239                                        I-centchroman 0.025 mg/kg/day                                                                       0.669 ± 0.149                                        I-centchroman 0.125 mg/kg/day                                                                       0.472 ± 0.126*                                       I-centchroman 0.625 mg/kg/day                                                                       0.430 ± 0.122*                                       I-centchroman 3.125 mg/kg/day                                                                       0.368 ± 0.124*                                       ______________________________________                                         Values are mean ± SD. *indicate significant reduction of prostate glan     weight compared to saline treated rats.                                  

We claim:
 1. A method for treatment or prophylaxis of benign prostatichypertrophy comprising administering to an adult male patient in need ofsuch treatment or prophylaxis a compound of formula I ##STR2## whereinR1, R4, and R5 are individually hydrogen, hydroxy, halogen,trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (loweralkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or apharmaceutically acceptable salt thereof in a range of from about0.001-75 mg/kg patient per day.
 2. The method according to claim 1 inwhich R1 is lower alkoxy.
 3. The method according to claim 1 wherein R1is methoxy.
 4. The method according to claim 1 wherein R2 is methyl. 5.The method according to claim 1 wherein R3 is methyl.
 6. The methodaccording to claim 1 wherein R4 is hydrogen.
 7. The method according toclaim 1 wherein R5 is a group having formula II below: ##STR3##
 8. Themethod according to claim 1 wherein said compound has the formula III:##STR4## .
 9. The method according to claim 1 wherein said compound isan isolated d- or 1-enantiomer.
 10. The method according to claim 1wherein said compound is an isolated 1-enantiomer.
 11. The methodaccording to claim 1 wherein said compound is3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl!-7-methoxychroman shown in formulaIV below: ##STR5## .
 12. The method according to claim 1 wherein saidcompound is an isolated d- or 1-enantiomer of3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl!-7-methoxychroman.
 13. The methodaccording to claim 1 wherein said compound is1-3,4-trans-2,2-dimethyl-3-phenyl-4-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl!-7-methoxychroman.
 14. The methodaccording to claim 1 wherein said compound is administered orally. 15.The method according to claim 1 wherein said compound is administered ina range from about 0.01 to 75 mg/kg patient per day.
 16. The methodaccording to claim 1 wherein said compound is administered in a rangefrom about 0.01 to 50 mg/kg patient per day.
 17. The method according toclaim 1 wherein said compound is administered one or more times per dayor week.
 18. The method according to claim 1 wherein said compound isadministered in the form of a dermal implant.